A cognitive disorder, or dementia, is a condition where developed intelligence deteriorates due to some acquired cause, resulting in a hindrance to social adaptation. Cognitive disorders are classified as neurodegenerative diseases, vascular cognitive diseases, prion diseases, infectious diseases, metabolic/endocrine diseases, trauma and cerebral surgical diseases, and toxic diseases (see Toshifumi Kishimoto & Shigeki Takahashi (Edit.), “STEP Series Seishinka” (Japanese document), 2th Edition, Kaibashobo, 2008, pp. 103-104). There were about 2.1 million dementia patients in Japan as of 2010, with a morbidity prevalence rate of about 8 to 10%, or even more than 10%, among the elderly over age 65, and this has been recognized as a serious problem in the worldwide aging society (Takashi Asada, “Igaku no Ayumi” (Japanese document), supplementary volume, “Cognitive disorders”, Ishiyaku Publishing, 2011, pp. 5-10). Data on underlying diseases of cognitive disorders indicate that the majority are neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), with about 35% being AD, about 15% being a combination of AD and cerebrovascular disease, and 5% being FTLD (Id.) Cognitive disorders associated with neurodegenerative diseases are characterized by insidious onset of memory impairment and/or personality changes which progresses over a period of at least six months or more. Neurodegenerative processes correlate highly with the degree of impairment of cognitive function, and a consistent characteristics involved therein is the presence of neurofibrillary tangles (NFT) (Alistair Burns et al. (Edit.), Dementia, 3rd Edition, 2005, CRC Press, pp. 408-464).
The tau protein is a protein encoded by the MAPT gene, which is located on chromosome 17 (17q21) in the human genome. Tau protein is one of the microtubule-binding proteins abundantly expressed in the central nervous system. The tau has been found to be a major constituent protein in the paired helical filaments and straight filaments forming NFT in AD, one of the most prominent neurodegenerative diseases, and its intracellular accumulation has been demonstrated in a variety of neuropathological conditions.
Tau was first implicated in neurodegenerative diseases based on the relationship between mutations in the MAPT gene and accumulation of tau in chromosome 17-linked frontotemporal dementia with Parkinsonism (FTDP-17). More than 40 gene mutations in the MAPT gene have been reported in relation to FTDP-17 (Tetsuaki Arai, “Shinkei Naika” (Japanese document), Vol. 72, special number, (Suppl. 6), 2010, pp. 46-51). These gene mutations are suggested as altering the proportions of tau isoforms or altering the structure and changing the interaction between mutant tau and microtubules, thus contributing to development of pathology. However, unlike familial neurodegenerative diseases, mutations in MAPT are rarely observed in sporadic neurodegenerative diseases such as AD. In addition, tau accumulated in neurodegenerative diseases is characterized by being highly modified via phosphorylation. Moreover, in patients exhibiting mild cognitive impairment (MCI), a correlation is observed between the level of phosphorylated tau in the spinal fluid and the degree of pituitary atrophy, suggesting phosphorylated tau as a highly reliable biomarker for neurodegeneration in patients with tauopathy (Wendy Noble et al., Expert Opinion on Drug Discovery, 2011, Vol. 6, No. 8, pp. 797-810). Based on these findings, attempts have been made to develop a treatment using inhibitors against kinases, which are enzymes involved in phosphorylation, and particularly against GSK-3 beta, for inhibiting excessive phosphorylation of tau (Id). However, there is a concern about possible side effects, since kinases such as GSK-3 beta are implicated not only in pathological conditions, but also in function controls in normal physiological processes. In fact, some of the sites where tau is phosphorylated by GSK-3 beta coincide with sites of tau phosphorylation seen in fetal and normal human brains (Burnes, et. al., supra) suggesting the possibility that this strategy may affect normal tau function.
Although it was believed that extracellular tau originates from leakage from degenerated nerve cells as a consequence of cell death, recent studies have suggested that following excessive intracellular phosphorylation, tau is processed and then actively secreted out of the cell. Phosphorylated tau secreted from the cell is thought to be dephosphorylated at certain phosphorylation sites and subsequently to act on muscarine receptors M1 and M3 of surrounding cells, thus resulting in various effects such as promoting intracellular tau phosphorylation and contributing to cell death (Miguel Diaz-Hemandes et al., Journal of Biological Chemistry, 2010, Vol. 285, No. 42, pp. 32539-32548 and Venessa Plouffe et al., PLoS ONE, 2012, Vol. 7, p. 36873). Experiments relating to immunotherapy for tauopathies using tau protein as the target have been reported, as attempts aimed at executing specific action against tau (see Noble, supra, Kishimoto, supra, Asada, supra and Burns, supra).
The major symptoms in human cognitive disorders are memory impairment and cognitive function impairmen, which is especially important given the role of cognitive function in memory-based judgment, communication and performance. Motor function, on the other hand, while being a symptom found in chromosome 17-linked frontotemporal dementia with Parkinsonism (FTDP-17) and terminal-stage Alzheimer's disease, is not necessarily a major symptom exhibited in cognitive disorders. Therefore, the main issue to be considered for treating cognitive disorders is improvement of cognitive functions. However, there is currently suitable animal models for testing tauopathy-associated cognitive function impairment that would allow identification of a therapeutic or prophylactic agent for treating cognitive disorders. In addition, no such agent exists that exhibits specific and superior effects against cognitive disorders.
In view of the therapeutic and prophylactic applications against cognitive disorders in human subjects, there is a demand for a humanized anti-phosphorylated tau antibody which not only has high binding affinity to phosphorylated tau, but also exhibits reduced antigenicity to the human body.